CKS1B amplification is a frequent event in cutaneous squamous cell carcinoma with aggressive clinical behaviour

Abstract

Genetic mechanisms giving rise to the development of cutaneous squamous cell carcinoma (cSCC) are poorly understood and development of genomic high resolution techniques has led to a better knowledge of the genetic basis of several human cancers. In this study, 16 cSCC were analyzed using array comparative genomic hybridization (arrayCGH). The most common aberrations found were gains of 3q11q13, 1q21.3q25, 13q34, and 19p13, and losses of 1p36p31, 3p24p21, 10p15q22, and 13q11q21. We detected gains (3/16) and amplification (1/16) of the 1q21.1q21.3 region. A potential candidate gene in this region, CKS1B (1q21.2), was selected for validation in an independent cohort and correlations with clinicopathological features were carried out. CKS1B gene and protein status were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in a series of 53 cSCC, 22 actinic keratoses (AK), and 10 normal skin samples. cSCC presented a higher frequency of chromosome 1 polysomy than AK (70% vs. 46%, P = 0.047). Association between CKS1B protein overexpression and both polysomy and amplification was demonstrated in cSCC (P < 0.001). Regarding amplifications, 11 cSCC patients (21%) presented CKS1B gene amplification. Interestingly, 8/11 (73%) patients who showed a CKS1B amplification had presented metastatic spread (mcSCC). Differences between the presence of CKS1B amplification and the presence or absence of mcSCC were observed (mcSCC [8/14] vs. cSCC [3/39]) (P < 0.001). Several drugs targeting CKS1B have been reported and may be useful for treating patients with cSCC and CKS1B amplifications.

Identification of Multiple DNA Copy Number Alterations Including Frequent 8p11.22 Amplification in Conjunctival Squamous Cell Carcinoma

“…31 We also examined if any DNA changes in our cases could be linked to cutaneous SCC or HPV-associated cervical and oropharyngeal carcinomas, and a summary of relevant recurring chromosomal abnormalities is shown in Supplementary Table S4. [32][33][34][35][36][37][38][39][40][41][42] Similarities include DNA gains that we observed in 3q22.3-3q28 and in 5p, as well as DNA losses in 9p, 13q, 17p, and 18q, which also are found in cutaneous SCC. 34 A smaller number of changes, which were similar in our tumors and HPV-associated neoplasms outside the eye are also listed in Supplementary Table S4.…”

Active nuclear IKK correlates with metastatic risk in cutaneous squamous cell carcinoma

“…In this sense, epidermal growth factor receptor (EGFR) overexpression has been associated with metastatic potential in cSCC [11], but it is also frequently found in non-metastatic cSCC and its utility as a prognostic marker is controversial [41]. CKS1B gene amplification (determined by fluorescence in situ hybridization) has also been associated with metastatic risk in cSCC [35], and we previously reported an association between the expression of epithelial to mesenchymal transition (EMT) markers and the risk of lymph node metastasis. However, we found that EMT proteins that are upregulated in the primary aggressive tumours are subsequently repressed in the metastases, which preclude their use as therapeutic targets [44].…”

Cks1: Structure, Emerging Roles and Implications in Multiple Cancers

“…Cks1 has been implicated in development of oral squamous cell carcinoma [131–133], salivary gland tumors [106], esophageal carcinomas [80,134,135], gastric carcinoma [20,136], colorectal carcinoma [108], gall bladder carcinoma [137] and hepatocellular carcinoma [19, 138–142]. Similarly Cks1 is believed to play a role in development and progression of several other types of cancers such as endometrial cancer [143], ovarian tumors [144–147], prostate cancer [148], testicular cancer [149], non small cell lung carcinomas (NSCLC) [111,150], cutaneous squamous cell carcinoma [151], melanoma [15], urothelial carcinoma and renal cell carcinomas [152,153], glioblastoma and CNS tumors [154,155], head and neck carcinoma [156], fibrosarcoma [157], and myxofibrosarcoma [158]. In many of these studies there is often a distinct correlation between Cks1 expression and clinicopathologic features such as tumor grade, stage, metastasis, loss of tumor differentiation patient prognosis and cancer free survival.…”